Design, synthesis and biological evaluation of piroctone olamine-derived iron chelators as HIF-1α stabilizers for diabetic wound healing.

Abstract

Hyperglycemia-induced iron overload and oxidative stress impair HIF-α stabilization and transcriptional activation, thereby suppressing neovascularization and delaying diabetic wound healing. Targeting iron-associated oxidative stress and reactivating HIF signaling therefore represents a promising therapeutic strategy for diabetic wound healing. In this study, inspired by the strong iron-chelating capacity of cyclic hydroxamate scaffolds, we designed and synthesized a novel series of 29 piroctone olamine-derived iron chelators through pharmacophore-guided optimization of the cyclic hydroxamate moiety and strategic incorporation of 2-oxoglutarate-mimetic motifs. Systematic structure-activity relationship analysis revealed that the free cyclic hydroxamate moiety, terminal aromatic substitution, and linker length were key determinants of iron-chelating potency, ROS-suppressive activity, cellular efficacy, and safety. Among these derivatives, compound 17b displayed the most favorable pharmacological profile, including potent iron-chelating activity, effective suppression of hyperglycemia-induced ROS accumulation, low cytotoxicity, and rapid stabilization of HIF-1α under high-glucose stress conditions. Further mechanistic investigations demonstrated that 17b activated HIF-dependent transcription, as reflected by increased expression of VEGFA and GLUT1. Functionally, 17b promoted fibroblast migration in vitro, supporting its role in key cellular processes involved in wound repair. In a Pseudomonas aeruginosa-infected diabetic rat wound model, 17b significantly accelerated wound closure, accompanied by enhanced neovascularization and collagen deposition. Collectively, these findings identify 17b as a promising piroctone olamine-derived HIF-1α stabilizer and an iron-chelating compound that may alleviate iron-associated oxidative stress under diabetic stress conditions, providing a novel chemical scaffold for the development of iron chelator-based therapeutics for diabetic wound management.